Literature DB >> 35020766

Descriptive study of chest x-ray examination in mandatory annual health examinations at the workplace in Japan.

Yuya Watanabe1, Toru Nakagawa1, Kota Fukai2, Toru Honda1, Hiroyuki Furuya2, Takeshi Hayashi1, Masayuki Tatemichi2.   

Abstract

The utility of chest x-ray examination (CXR) in mandatory annual health examinations for occupational health is debatable in Japan. This study aimed to provide basic data to consider future policies for mandatory annual health examinations in the workplace. A nationwide descriptive survey was performed to determine the rate of detection of tuberculosis, lung cancer, and other diseases through CXR in organizations associated with National Federation of Industrial Health Association. The rate of finding on CXR conducted during annual health examinations in FY2016 was evaluated. Data regarding diagnosis based on follow-up examination findings were obtained and compared with the national statistics. In addition, CXR findings were compared with the results of low-dose lung computed tomography performed at the Hitachi Health Care Center. From 121 surveyed institutions, 88 institutions with 8,669,403 workers were included. For all ages, 1.0% of examinees required follow-up examination. Among 4,764,985 workers with diagnosis data, the tuberculosis detection rate was 1.8-5.3 per 100,000 persons. For Lung cancer, 3,688,396 workers were surveyed, and 334 positive cases were detected. The lung cancer detection rate using CXR was 9.1-24.4 per 100,000 persons. From 164 cases with information regarding the clinical stage, 72 (43.9%) had Stage I lung cancer. From 40,045 workers who underwent low-dose computed tomography multiple times, 31 lung cancer cases, all with Stage I disease, were detected (detection rate: 77.4 per 100,000 persons). Our findings suggest that CXR plays a little role in the detection of active tuberculosis. With regard to LC screening, the detection rate of LC by CXR was lower, approximately 50%, than the expected rate (41.0 per 100,000 persons) of LC morbidity based on the age-sex distribution of this study population. However, the role of CXR for LC screening cannot be mentioned based on this result, because assessment of mortality reduction is essential to evaluate the role.

Entities:  

Mesh：

Year:  2022        PMID： 35020766      PMCID： PMC8754336          DOI： 10.1371/journal.pone.0262404

Source DB:  PubMed          Journal:  PLoS One        ISSN： 1932-6203            Impact factor:   3.240


Introduction

Periodic chest x-ray examination (CXR) in occupational settings has been conducted for active tuberculosis (TB) screening since 1972, as required by the Industrial Safety and Health Law [1], subsequent to the TB Prevention Law of 1950 in Japan. The usefulness of CXR in mandatory annual health examinations has been vigorously discussed; however, there is no consensus on whether it should be a mandatory examination for all workers aged ≥40 years [2]. In particular, as the incidence of TB has declined, the significance of CXR TB screening has been increasingly debated [2]. In recent years, the digitalization of chest photographs has been promoted instead of mass miniature radiography (MMR), and the detection rate is expected to be consequently improved [3]. It is undeniable that the primary purpose of CXR in the workplace is to detect workers with active TB [1]. In 2016, the prevalence of TB had decreased to 13.9 per 100,000 people in Japan [4]. However, in 2015, with the aging of the working population, the prevalence of lung cancer (LC) had increased to 8.8–278.5 in men and 6.9–111.3 in women in the age group of 40–69 years [5]. The usefulness of any examinations for screening depends on the pre-test probability and accuracy of findings [6]. Therefore, the clinical utility of CXR should be discussed as relevant in each era. In addition to these two major diseases, much information can be obtained from CXR in the clinical situation. CXR can detect not only occupational lung diseases, such as pneumoconiosis, obstructive pulmonary disease, pneumonia, mediastinal tumor, pneumothorax, and pleural effusion, but also atherosclerotic lesions, cardiac enlargement, aortic aneurysms, and so on. However, it is necessary to evaluate the significance of the annual CXR from various perspectives. Therefore, there has been much debate on the need for CXR in the mandatory health examinations at the workplace [7,8]. Japanese guideline for lung cancer screening recommends CXR [9]. Thus mandatory CXR in workplace plays a role in lung cancer screening in addition to screening for TB. The first priority of evaluation of effectiveness on cancer screening must be based on randomized controlled trials (RCT) using mortality as outcome. Theoretically the detection number of cancers is not useful outcome to evaluate effectiveness, because cancers detected by screening can include cases with overdiagnosis. Thus this study did not aim to evaluate the effectiveness of CXR for cancer screening. The purpose of this study is to provide actual descriptive data on the current state of social implementation of the screening as a measure, not directly to assess the effectiveness of CXR for the cancer screening. To provide basic data of mandatory annual workplace CXR screening for workplace health, we conducted a nationwide descriptive survey to determine the detection rate of TB, LC, and other diseases through CXR.

Participants and methods

CXR

National Federation of Industrial Health Organization (NFIHO) contracted with 121 occupational health organizations or institutions (across 43 of the 47 prefectures in Japan) that were eligible for collection of the CXR results. NFIHO comprises the largest group of occupational health organizations that conduct legally mandated health examinations, provide health guidance, and issue occupational health improvement guidance based on the Japanese Industrial Health and Safety Law. Moreover, NFIHO plays an important role in ensuring quality control of medical tests for over 46 million of the 56 million workers in Japan, including the annual mandatory health examinations of 14 million individuals. From the occupational health organizations or institutions associated with NFIHO that responded positively to our request, we obtained data regarding the actual number of CXRs performed (regardless of whether they were digital or analog x-rays), the number of findings, and the number of examinees who required follow-up examinations during mandatory health examinations, including comprehensive workplace health check-up, for the period from April 2016 to March 2017. Data were collected for all examined workers and for workers aged ≥40 years. The number of examinees who required further follow-up examinations and the number of examinees suspected to have TB were investigated, and the rates for each parameter were calculated. In addition, when examinees could be followed up and had a definitive diagnosis, such as TB, LC, or other diseases, additional information was obtained. The rates of detection for TB and LC were calculated from the number of examinees who were diagnosed with active TB and LC, respectively. Concerning LC, data regarding the histopathological type and clinical stage were recorded. Furthermore, details of diseases other than TB and LC that necessitated further follow-up examination were extracted.

Low-dose computed tomography (LDCT) screening for LC

Detailed information on LDCT screening has been described in previous reports [9-11]. Briefly, since April 1998, LDCT has been performed at the Hitachi Health Care Center for individuals aged ≥50 years. From April 1998 to December 2006, the imaging was performed on a single-row CT (conditions: 120 kV, 50 mA, 10 mm collimation, pitch 2). From January 2007, a new model with 4-row multi-detector row CT was used (3.75 mm × 4 rows, 120 kV, 20 mA, 5-mm collimation, pitch 5, computed tomography dose index: 1.4 mGy). From the beginning of 1998, the system was implemented using a comparative reading system and a double reading system. In cases of examinees who required follow-up examinations, further investigations were conducted at the Hitachi General Hospital. In the present study, we collected the results for 10 years from April 1998 to March 2009. We subdivided the examinees into groups of those who underwent one CT screening and those who underwent two or more CT examinations, and tabulated the number of detailed examinations. Moreover, data regarding the cancer pathology and clinical stage were obtained, and the results from 2016 to 2018 were aggregated to evaluate the latest rate of detection.

Information on death due to LC

Details of workers who died of LC from April 2010 to March 2018 were retrospectively examined with regard to information on the history of LDCT, histological types, and clinical stage. These abovementioned data were obtained from the death certificate of the worker, and the worker’s examination history of LDCT was traced back up to 2 years and details of smoking status were also obtained. This study was approved by the Tokai University School of Medicine Clinical Research Review Board (approval no. 16R-076, 19R-228). In the survey, information on the number of CXRs and LDCTs that were conducted and the number of findings was collected. None of the abovementioned data contained personal information, and there was no possibility of violation of patient confidentiality or personal information being accessed. Thus, the need for informed consent was waived.

Statistical analysis

For CXR, the rate of follow-up examinations and the rate of detection of TB and LC were calculated from the number of examinees that required follow-up examination, were suspected to have TB, were diagnosed with TB or LC as a numerator, and undertook CXR as a denominator. The rate obtained by dividing the number of examinees who actually underwent follow-up examinations by that of examinees who required follow-up examination was defined as the rate of follow-up examination. The estimated rate of detection was calculated by dividing the actual rate of detection by the rate of follow-up examination. These data were expressed as the number of findings per 100,000 persons. The age–sex distribution over 5 years for examinees who underwent CXR in occupational health organizations or institutions associated with NFIHO were separately collected. The expected incidence rate was calculated from the reports of the Japanese government concerning TB [4] or cancer statistics database [6]. The 95% confidence interval (CI) was determined using the Agresti–Coull method.

Results

With the cooperation of 88 facilities (72.7%) from 121 affiliated members of NFIHO, we included data from a total of 8,594,676 workers (men: 5,461,011, women: 3,133,665) in this study. The prevailing rate of analog CXR was 18.9%. The rates of workers who were aged ≥40 years were 57.7% and 59.5% in men and women, respectively. The results of CXR are shown in Table 1. Of the 5,461,011 men examined, the rate of abnormal findings was 9.1% (498,351) and that of examinees who required re-examination was 0.6%. The rate of examinees who required further follow-up examinations was 1.1%, and the suspicion rate for TB was 0.0068%. Among the 3,133,665 women, the rate of abnormal findings was 6.7%, and the rate of examinees who required re-examination was 0.49%. The rate of examinees who required further follow-up examinations was 0.9%, and the suspicion rate for TB was 0.0056%.
Table 1

Results of chest x-ray examination.

All age groups≥40 years
MenWomenTotalMenWomenTotal
Examinees5,461,0113,133,6658,594,6763,192,5081,854,7505,047,258
Number of participants with abnormal findings498,351210,339708,690376,010159,435535,445
Rate of abnormal findings9.1%6.7%8.2%11.8%8.6%10.6%
Number of participants who required follow-up examinations58,13027,01685,146484902591274402
Rate of participants who required follow-up examination1.10%0.86%0.99%1.50%1.4%1.47%
Number of participants who had findings suspicious for tuberculosis374176550317125442
Rate of participants who had findings suspicious for tuberculosis (per 100,000 persons)6.85.66.49.96.78.8
95% confidence interval6.2–7.54.8–6.55.8–6.98.8–11.05.5–7.97.9–9.6

Detection of tuberculosis

Forty-four institutions had follow-up data on the precise diagnosis, and data from 4,764,985 individuals (2,991,434 men, 1,773,551 women) of all ages were available for the calculation of the TB detection rate. Table 2 shows the results of the calculations. Of the 10,460 men and 6,174 women of all ages who underwent follow-up examinations and were diagnosed, 88 cases (59 men, 29 women) were determined to have active TB. The positive predictive value (PPV) was primarily calculated to be 0.18% (88/47,962). This value might have been an underestimation, because the cases that could be followed up were 16,734 (34.9%). Thus, the maximum PPV was calculated as 0.56% (88/16734), which might have been an overestimation. Plausible PPV was estimated to range between 0.18% and 0.56%. Overall, the detection rates of TB were 2.0 and 1.5 per 100,000 persons in men and women, respectively. In total, 88 cases were detected in this study, suggesting that the detection rate was 1.8 (95% CI: 1.5–2.2) per 100,000 persons. As the rate of examinees who could be followed up was 32.8% in men and 39.0% in women, the detection rate was approximately estimated to be 5.3 (95% CI: 4.6–5.9) per 100,000 persons (calculated as follows: [59/0.328+29/0.90]/4,764,985).
Table 2

Detection of tuberculosis and other diseases using chest x-ray examination among participants who were followed up for information on detailed examination.

All ages≥40 years
MenWomenTotalMenWomenTotal
Examinee2,991,4341,773,5514,764,9851,757,1421,048,6462,805,788
Number of participants who required follow-up examination31,89116,07147,96226,33916,82743,166
Rate of follow-up examination requirement1.07%0.91%1.0%1.50%1.60%1.54%
Number of participants who underwent follow-up examination10,4606,27416,7347,3094,88012,189
Rate of follow-up examination32.8%39.0%34.9%27.7%29.0%28.2%
Number of cases diagnosed with tuberculosis592988361753
Positive predictive value for tuberculosis screening Actual PPV (maximum) PPV)*0.19% (0.56%)0.18% (0.46%)0.18% (0.53%)0.14% (0.49%)0.14% (0.35%)0.12% (0.43%)
Rate of detection of tuberculosis (per 100,000 persons)2.01.61.82.01.61.9
95% confidence interval1.5–2.51.0–2.21.5–2.21.4–2.70.8–2.41.4–2.4
Estimated rate of tuberculosis (per 100,000 persons)**6.04.25.37.45.66.7
95% confidence interval5.1–6.93.2–5.24.6–5.96.1–8.74.1–7.05.7–7.7
Number of participants with x-ray findings of other diseases3,2462,0505,2962,7191,8254,544
Rate of other diseases0.11%0.12%0.11%0.15%0.17%0.16%

*Maximum PPV was calculated by the actual PPV divided by the rate of follow-up examination.

** The estimated rate of tuberculosis was calculated by the number of cases diagnosed with tuberculosis divided by the rate of follow-up examination.

PPV, positive predictive value.

*Maximum PPV was calculated by the actual PPV divided by the rate of follow-up examination. ** The estimated rate of tuberculosis was calculated by the number of cases diagnosed with tuberculosis divided by the rate of follow-up examination. PPV, positive predictive value. According to the national database of TB in 2016 [4], the incidence rate of TB was 13.9 per 100,000 persons. Moreover, the rate of new TB patients among workers was 57.0% [4], and the estimated incidence rate among workers was 13.9×0.57 = 7.9 per 100,000 persons. According to the stratification of the TB incidence rate by age–sex in 2016 [4], the expected incidence of TB was calculated to be 9.1 (95% CI: 8.2–9.9) per 100,000 persons based on the age–sex distribution of NFIHO (S1 Table).

Detection of LC

With regard to LC, 38 institutes had follow-up data on precise diagnoses. Moreover, data from 3,688,365 individuals (2,295,702 men, 1,392,693 women) of all ages were available (Table 3). Of 25,442 men and 12,704 women who were screened and found to require follow-up examination for LC, 8,849 men and 5,288 women underwent detailed examinations. The rates of institutional follow-up examinations were 34.8% and 41.6% in men and women, respectively.
Table 3

Detection of lung cancer using chest x-ray examination among participants who were followed up for information on detailed examination.

All ages≥40 years
MenWomenTotalMenWomenTotal
Examinee2,295,7021,392,6933,688,3951,385,574832,9012,218,475
Number of participants who required follow-up examination25,44212,70438,14621,20814,02635,234
Rate of follow-up examination requirement1.11%0.91%1.0%1.53%1.68%1.59%
Number of participants who underwent follow-up examination8,8495,28814,1376,0274,07710,104
Rate of follow-up examination34.8%41.6%37.1%28.4%29.1%28.7%
Number of cases diagnosed with lung cancer23410033422898326
Positive predictive value for lung cancer screening Actual PPV (maximum PPV)*0.92% (2.64%)0.79% (1.89%)0.88% (2.39%)1.08% (3.78%)0.70% (2.40%)0.93% (3.23%)
Rate of detection of lung cancer (per 100,000 persons)10.27.29.116.511.814.7
95% confidence interval9.1–11.85.7–8.68.2–10.214.3–18.69.4–14.113.1–16.3
Estimated rate of lung cancer (per 100,000 persons)**29.317.324.457.940.551.2
95% confidence interval27.8–32.315.1–19.423.2–26.553.9–61.936.1–44.848.3–54.2

* Maximum PPV was calculated by the actual PPV divided by the rate of follow-up examination.

**The estimated rate of lung cancer was calculated by the number of cases diagnosed with lung cancer divided by the rate of follow-up examination.

PPV, positive predictive value.

* Maximum PPV was calculated by the actual PPV divided by the rate of follow-up examination. **The estimated rate of lung cancer was calculated by the number of cases diagnosed with lung cancer divided by the rate of follow-up examination. PPV, positive predictive value. Subsequently, 334 cases were diagnosed as LC, and the detection rate was 9.1 (95%CI: 8.1–10.0) per 100,000 persons. Overall, the total number of participants diagnosed with LC was estimated to be 672 (234/0.348) in men and 240 (100/0.416) in women, and a total incidence rate of 24.7 (95% CI: 22.8–26.0, 912/3,688,395) per 100,000 persons was noted. According to the LC incidence rate in 2015 stratified by age–sex [4], based on the age–sex distribution of NFIHO data (S1 Table), the expected LC incidence rate was 41.0 (95% CI: 39.2–42.9) per 100,000 persons. Of the 344 LC cases, pathological and clinical stage information was obtained from 164 cases; 72 (43.9%) had Stage I disease, 21 (12.8%) had Stage II, and 32 (19.5%) had Stages III or IV. With regard to pathology, 123 (74.5%) cases were adenocarcinomas, 29 (17.6%) were squamous cell carcinomas, five (3.0%) were small cell carcinomas, and one (0.6%) was a large cell carcinoma (Table 4).
Table 4

Clinical stage and pathology of lung cancer detected by chest x-ray and low-dose CT screening.

Chest X-rayLow-dose CT screening
First examinationSecond or later examinationsTotal
Examinee2218475*15,52540,04555,570
Number of cases diagnosed with lung cancer326*603191
Rate of detection of lung cancer (per 100,000 persons)51.2**386.577.4163.8
95% confidence interval48.3–54.2287.4–485.649.3–105.5130.0–197.7
Clinical stageI72593190
II21000
III32101
IV32000
Metastasis7000
Unknown170000
Total334***603191
PathologyAdenocarcinoma123572885
Squamous cell29022
Small cell5011
Large cell1202
Metastasis7000
Others0101
Unknown169000
Total334603191

* ≥40 years.

** Estimated rate (see Table 4).

*** All aged workers who were diagnosed with lung cancer.

* ≥40 years. ** Estimated rate (see Table 4). *** All aged workers who were diagnosed with lung cancer.

LDCT screening

Table 4 shows the results of LDCT. The first examination detected 60 cases with LC, and the rate was 386 (95% CI: 287.4–485.6) per 100,000 persons. Second or later examinations revealed that the detection rate was 77.4 (95% CI: 49.3–105.5) per 100,000 persons, and 31 cases (100%) exhibited clinical Stage I disease. Fig 1 shows the association between the numbers of times that examinees underwent LDCT and the rate of detection, which decreased in proportion to the number of times LDCT was conducted.
Fig 1

Number of times that the examinees underwent screening with low-dose lung computed tomography scanning, and the rate of detection.

S2 Table shows the recent (2016–2018) number of patients who underwent LDCT on stratification by age–sex, the number of required follow-up examinations, and number of LC. Of the 11,632 (10,257 men and 1,375 women) patients, three cases with LC were detected, and the incidence rate was 25.8 (95% CI: 00.0–63.1) per 100,000 persons. Based on the age–sex distribution of recent Hitachi data, the expected LC incidence rate was 155.2 (95% CI: 80.3–230.9) per 100,000 persons.

Death due to LC

During the follow-up period from 2010 to 2018, 17 workers died because of LC. The pathologic diagnosis, clinical stage, and history of LDCT screening are shown in S3 Table. Of the seven workers who died of small cell carcinoma, three (42.9%) men had a history of LDCT screening. In addition, all of them had a history of current or past smoking. Of the five patients who died because of adenocarcinoma, one (20%) had a history of LDCT screening.

Detection of other diseases

S4 Table lists the findings, other than TB and LC, which were identified in this study among 4,764,985 workers (2,991,434 men, 1,773,551 women). The numbers of cases of patients with emphysema, nontuberculous mycobacteriosis, mediastinal tumor, sarcoidosis, pulmonary fibrosis, aortic aneurysm, and interstitial pneumonia are presented. Cases of emphysema or nontuberculous mycobacteriosis were most often detected (rates, 0.40 [95% CI: 0.15–0.64] per 100,000 persons in men and 0.12 [95% CI: 0.07–0.18] in women).

Discussion

This descriptive epidemiological survey reveals that the rate of TB detection among workers in Japan by mandatory annual CXR was estimated to be 1.8–5.1 per 100,000 persons. The number of new TB patients in the occupational workforce in 2016 was estimated to be 7.9 per 100,000 persons [4], and the expected morbidity rate from the age–sex distribution in this study population was 9.1 per 100,000 persons (including non-workers). From these results, the detection rate of TB by CXR was considered to be lower than the expected morbidity. According to statistics from the Tuberculosis Surveillance Center of the Tuberculosis Research Institute, the rates of new cases identified from annual workplace health examinations, stratified by age, were reported to be 18.3%, 22.7%, 19.7%, 15.6%, and 6.0% for examinees in their 20s, 30s, 40s, 50s, and 60s, respectively [4]. Moreover, the latent period for TB has been reported to range from 1 or 2 months to 2 years, but most patients develop symptoms within 6 months [12]. Therefore, it is impossible to identify all instances of TB onset by annual CXR. Considering the national database statistics and the natural course of TB, it is difficult to appreciate the usefulness of routine annual CXR examination to detect TB in countries with low TB prevalence. Thus, the contribution of CXR to tuberculosis infection control might not be significant. The mass miniature radiophotography (MMR) sensitivity and specificity of CXR for the diagnosis of active TB were in the ranges of 64%–80% and 52%–63%, respectively, and thus, the investigation cannot be considered the gold standard for TB screening [13-16]. According to a recent study on the screening of immigrants, the sensitivity of CXR was reported to vary from 55.6% to 93% [17]. Our data showed that the positive predictive value of CXR for TB was 0.18%–0.56%, which was very low, given the low prevalence. The World Health Organisation aims to reduce the new TB cases by approximately 90% by 2035 and reduce the prevalence to <10 per 100,000 population [18]. From the perspective of cost-effectiveness, active case-findings for TB using CXR should be considered among high-risk populations. Nevertheless, the strategy should be re-considered when the prevalence is <10 per 100,000 persons in Japan [19]. Active case-findings among all general workers may be unnecessary. Next, CXR plays a role in LC screening because CXR is recommended by governmental regulations as an alternative to LC screening [20]. Our data showed that the detection rate was 9.1–24.4 per 100,000 persons. This rate was lower, approximately 50%, than the expected rate of 41.0 per 100,000 persons of LC morbidity based on the age–sex distribution of this study population. However, CXRs conducted in the workplace differ from those performed for LC screening because CXR for cancer screening basically requires a comparative reading and a double reading [20,21]. In addition, sputum cytology must be performed for those with a smoking index of more than 600, but this has not been undertaken in annual health examinations in the workplace [21]. Furthermore, CXR in occupational areas are conducted annually, and were performed as an almost non-initial examination, which means that almost all participants had been undergoing CXR every year. Thus, these different situations may be potentially underestimated. However, outcomes for the effect of cancer screening must be addressed by mortality, but not by increased numbers of diagnosis and more localized stages, because cancer screening has several biases and harmful effects such as overdiagnosis [22,23]. Regarding to LC screening, the main problem of CXR was reported to be a low sensitivity, while, that of LDCT was overdiagnosis [24]. Thus, using our data on this study, we cannot compare or evaluate the screening effects between CXR and LDCT. We only provided descriptive data as reference values. In Japan, Nawa et al. reported that LDCT among residents and workers had numerous advantages [10,11,25,26]. Recently, a population-based cohort study has been published by Hitachi City, Ibaraki Prefecture, and the LC mortality decreased by 51% in the group that was screened using LDCT than in the group screened using CXR [26]. Reports from two meta-analyses show that, compared with CXR, LDCT was more effective in reducing LC mortality [27,28]. In a randomized control trial conducted by the National Lung Screening Trial, the mortality in the LDCT group was reduced by 20% compared with that in the CXR group [29]. Furthermore, the European Union issued a statement to establish an LC screening system with LDCT [30]. Furthermore, challenges of LC screening using LDCT include the high cost and the high rate of false-positives due to the high sensitivity [31]. Therefore, previous reports have recommended that LDCT should be applied to high-risk populations, such as those over 50 years or smokers, to increase the prior probability [29,30]. At the beginning of LDCT screening in the Hitachi Health Care Center, a high detection rate of 384 per 100,000 persons was observed, despite the fact that CXRs were conducted yearly, which means that there were many cases of LC that could not be detected by CXR. In the 20 years of annual LDCT screening, the detection rate of LC has gradually decreased to 25.7 per 100,000 persons. This finding seems to indicate a limit of the annual detection rate for early LC, and is lower than the that (i.e., 155.2 per 100,000 persons) of expected morbidity, based on the age–sex distribution. This phenomenon is attributed to the characteristics of LDCT screening. Among many workers who annually undergo LDCT screening, suspected LC lesions were found in the first year. This is because LDCT is much more effective than CXR for detecting LC [10,11,25,26,32]. Most lesions found on LDCT were early LC (diameter, ≤20 mm) [10,11,25,26,32], and 6-mm nodules were detected [33]. Furthermore, a cohort study comparing the CT and CXR screening groups showed that LC deaths increased 5–7 years later in the CXR group than in the LDCT screening group [25]. Therefore, in the LDCT screening group, LC was detected more than 5–7 years earlier than in the CXR group [25,26]. Thus, as pointed out by the NLST, the morbidity and detection rates decreased in the subsequent yearly examination group. In addition, the lower detection rate with LDCT than the estimated morbidity indicates one of the limitations of LDCT screening. When examining the histological type of LC death, it is assumed that workers with small cell carcinoma did not survive, although LC was detected using LDCT. This was because small-cell LC progresses quickly, and the number of cases that can be detected in early stages using LDCT may be limited [34]. Therefore, appropriate screening methods for small cell LC should be considered as a future measure. CXR identified other diseases, such as emphysema, inflammatory changes, mediastinal tumors, pneumothorax, sarcoidosis, and aortic aneurysms. Moreover, the clinical utility should be considered separately from TB and LC. However, the incidence and/or prevalence rates of these diseases were very low. Thus, further investigations are needed to determine the cost-effectiveness of CXR for these diseases. This study had several limitations. First, this was a descriptive survey. This is because all CXR in Japan have historically been started and performed as TB screening for workers. The number of detections as cancer screening cannot be evaluated due to problems of harmful effects such as overdiagnosis. Thus, we could not effectively compare the usefulness of CXR and LDCT only based on our results. Second, only 38/88 institutions could follow-up the examinees who required follow-up examination. Moreover, only 30% of examinees were actually followed up. The estimated morbidity was described as a range, but accurate point estimation cannot be undertaken from our data. Third, the main results of LDCT were obtained from 1998 to 2008, and the results of the era might have been different for CXR. However, recent data from 2016 to 2018 did not differ considerably.

Conclusions

In conclusion, based on the actual detection rate of TB using CXR, we ascertained that CXR plays a little role in TB detection in the general workplace. In addition, variability and reproducibility are well-known issues for CXR interpretation. If an outbreak of clustered transmission occurs in the workplace or if some LC cases are overlooked, retrospective re-evaluation of cases with a documented diagnosis who were previously evaluated using CXR may reveal discrepancies and create issues for the radiologist who interpreted the CXR. With regard to LC screening, the detection rate with CXR was lower, approximately 50%, than the expected rate of LC morbidity based on the age–sex distribution of this study population. However, the results of this study do not evaluate actual utility for CXR in the mandatory annual health examinations. Further follow-up studies are needed to assess mortality reduction in workplace for LC screening. Reports from North America have shown a significant reduction of mortality regarding LDCT screening, and it will be considered in high-risk populations, such as those over 50 years with heavy smokers in workplaces. Our study, however, demonstrated that the effectiveness of LDCT screening was limited for patients with small cell carcinoma. Thus, strengthening smoking cessation measures in workplaces should be considered as well as screening.

Expected morbidity of tuberculosis and lung cancer based on age–sex distribution of 42 institutions associated with NFHA*.

(DOCX) Click here for additional data file.

Results of recent low-dose CT examinations in 2016–2018.

(DOCX) Click here for additional data file.

Characteristics of workers who died of lung cancer.

(DOCX) Click here for additional data file.

Diseases other than tuberculosis and lung cancer detected by chest x-ray examination.

(DOCX) Click here for additional data file. 17 May 2021 PONE-D-20-19580 Descriptive study of chest x-ray examination in mandatory annual health examinations at the workplace in Japan PLOS ONE Dear Dr. Tatemichi, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. ============================== The study seems well design and the manuscript well written. However, the reviewers do not totally agree with the interpretation of the data presented. Thus, I suggest major revision. ============================== Please submit your revised manuscript by Jul 01 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the The study seems well design and the manuscript well written. However, the reviewers do not totally agree with the interpretation of the data presented. Thus, I suggest major revision.The study seems well design and the manuscript well written. However, the reviewers do not totally agree with the interpretation of the data presented. Thus, I suggest major revision.The study seems well design and the manuscript well written. However, the reviewers do not totally agree with the interpretation of the data presented. Thus, I suggest major revision.The study seems well design and the manuscript well written. However, the reviewers do not totally agree with the interpretation of the data presented. Thus, I suggest major revision.The study seems well design and the manuscript well written. However, the reviewers do not totally agree with the interpretation of the data presented. Thus, I suggest major revision.The study seems well design and the manuscript well written. However, the reviewers do not totally agree with the interpretation of the data presented. Thus, I suggest major revision.The study seems well design and the manuscript well written. However, the reviewers do not totally agree with the interpretation of the data presented. Thus, I suggest major revision.office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols. We look forward to receiving your revised manuscript. Kind regards, Alessandra Giuliani Academic Editor PLOS ONE Additional Editor Comments: The study seems well design and the manuscript well written. However, the reviewers do not totally agree with the interpretation of the data presented. Thus, I suggest major revision. Journal Requirements: When submitting your revision, we need you to address these additional requirements. 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf 2. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. In your revised cover letter, please address the following prompts: a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information) and who has imposed them (e.g., an ethics committee). 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Thank you for stating the following in the Financial Disclosure section: [This study was supported by the Ministry of Health, Labour, and Welfare of Japan through an Industrial Disease Clinical Research Grants (grant no. 170301).]. We note that one or more of the authors are employed by a commercial company: Hitachi Health Care Center Please provide an amended Funding Statement declaring this commercial affiliation, as well as a statement regarding the Role of Funders in your study. If the funding organization did not play a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript and only provided financial support in the form of authors' salaries and/or research materials, please review your statements relating to the author contributions, and ensure you have specifically and accurately indicated the role(s) that these authors had in your study. 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We will change the online submission form on your behalf. Please know it is PLOS ONE policy for corresponding authors to declare, on behalf of all authors, all potential competing interests for the purposes of transparency. PLOS defines a competing interest as anything that interferes with, or could reasonably be perceived as interfering with, the full and objective presentation, peer review, editorial decision-making, or publication of research or non-research articles submitted to one of the journals. Competing interests can be financial or non-financial, professional, or personal. Competing interests can arise in relationship to an organization or another person. Please follow this link to our website for more details on competing interests: http://journals.plos.org/plosone/s/competing-interests [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Partly Reviewer #2: No ********** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ********** 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: No Reviewer #2: Yes ********** 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ********** 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: Dr. Watanabe analyzed the national occupational health examination database to appreciate the effectiveness of routine annual chest x-ray in Japan. The main findings were (1) Among the 4764985 participants who underwent chest x-ray examination for TB detection and follow-up data for diagnosis were available, 47962 subjects were advised for follow up, 16734 subjects underwent follow-up exam, and 88 patients were diagnosed of active TB (rate of detection 1.8/100000, positive predictive value 0.53%); (2) Among 3688395 participants who underwent chest x-ray for lung cancer detection, 38146 subjects were advised for follow-up examination, 14137 subjects underwent follow-up exam, and 334 cases were diagnosed with lung cancer (rate of detection 9.1/100000, positive predictive value 2.36%). (3) Stage I lung cancer accounted for 43.9% among the lung cancer revealed by annual chest x-ray examination. The authors concluded that chest x-ray examination plays a role in the detection of active TB and early stage lung cancer. The study is well design and the manuscript is well written. However, I do not totally agree with the interpretation of the data presented. I would suggest some minor revisions. 1. I am confused with the calculation of positive predictive value for TB detection and lung cancer. For the positive predictive value of chest x-ray to detect active TB, the authors use the number of cases diagnosed with tuberculosis (88) as the numerator and the number of participants who underwent follow-up (16734) as the denominator. Were all participants advised for follow-up examination due to suspicion of active TB? If yes, then the positive predictive value should be 88/47962 = 1.8%. If no, then the denominator should be the number of subjects whose chest x-ray were considered possible active TB. Similar issues existed in the calculation of positive predictive value of lung cancer detection. 2. According to the estimation by the authors (line 172 of the manuscript), the expected incidence of active TB for the population studied was 9.1/100000. However, the rate of detection was 1.8/100000. That means more than 80% of the cases of active were not detected by annual chest x-ray examination. With an extremely low positive predictive value (0.53%), it is difficult to appreciate the usefulness of routine annual chest x-ray examination for the purpose of TB detection in countries with low prevalence of TB. The variability and reproducibility were well-known issues for chest x-ray interpretation. If an outbreak of clustered transmission among work place occurs, retrospective re-evaluation of the chest x-ray with a documented diagnosis in mind may reveal some obscured abnormalities and cause trouble to the radiologist who firsthand interpreted the chest x-ray. Similar issues existed in the interpretation of usefulness of lung cancer detection with chest x-ray. At least, these concerns should be listed. 3. The expected incidence of lung cancer increases exponentially in the elderly. I suggest the authors to extend the table 3 by further stratifying the detection of lung cancer among age groups of <40, 40-60, and >60 years old. 4. The table 5 is not quite relevant to the topics of the present study. It is difficult to determine the accuracy, sensitivity, and specificity by chest x-ray examination for the diagnoses listed. I would suggest to remove the information of table 5 from the present report. 5. In line 256-258, the sentence “From the perspective of cost-effectiveness, screening for Tb should be considered when the prevalence is lower than 10 per 100,000 persons” is ambiguous. Reviewer #2: Numbers of diagnoses and stage are poor surrogate outcomes for the effect of health checks. Increased numbers of diagnosis and more localised stages can be and impact of a beneficial effect, a harmful effect (especially overdiagnosis) or both. Moreover, mortality rates in a non-randomised trial cannot be used as a result of benefits. Finally, survival rates will be biased due to lead time bias and leangt time bias (overdiagnosis bias) and are the not useful outcomes when it comes to early disease detection, e.g. screening and health checks. ********** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: Yes: John Brodersen [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. 19 Aug 2021 Reviewer #1: Dr. Watanabe analyzed the national occupational health examination database to appreciate the effectiveness of routine annual chest x-ray in Japan. The main findings were (1) Among the 4764985 participants who underwent chest x-ray examination for TB detection and follow-up data for diagnosis were available, 47962 subjects were advised for follow up, 16734 subjects underwent follow-up exam, and 88 patients were diagnosed of active TB (rate of detection 1.8/100000, positive predictive value 0.53%); (2) Among 3688395 participants who underwent chest x-ray for lung cancer detection, 38146 subjects were advised for follow-up examination, 14137 subjects underwent follow-up exam, and 334 cases were diagnosed with lung cancer (rate of detection 9.1/100000, positive predictive value 2.36%). (3) Stage I lung cancer accounted for 43.9% among the lung cancer revealed by annual chest x-ray examination. The authors concluded that chest x-ray examination plays a role in the detection of active TB and early stage lung cancer. The study is well design and the manuscript is well written. However, I do not totally agree with the interpretation of the data presented. I would suggest some minor revisions. Response: The authors would like to thank the reviewer for the feedback. We have made every effort to address the issues raised and to respond to all comments. The revisions are indicated in red color text in the revised manuscript. In addition, we have carried our English check by the native speakers again. Please, find next a detailed, point-by-point response to the comments below. Review１ 1. I am confused with the calculation of positive predictive value for TB detection and lung cancer. For the positive predictive value of chest x-ray to detect active TB, the authors use the number of cases diagnosed with tuberculosis (88) as the numerator and the number of participants who underwent follow-up (16734) as the denominator. Were all participants advised for follow-up examination due to suspicion of active TB? If yes, then the positive predictive value should be 88/47962 = 1.8%. If no, then the denominator should be the number of subjects whose chest x-ray were considered possible active TB. Similar issues existed in the calculation of positive predictive value of lung cancer detection. Response: As pointed out by the reviewer, active TB was detected in 88 patients. Thus, the PPV was actually 0.18% (88/47962). However, we could follow up only 16734 (34.9%) participants who underwent follow-up examination. The measured PPV of 0.18% was the lowest PPV and might have been underestimated. The maximum PPV was calculated as 0.56% (88/16734), which might have been overestimated. Thus, plausible PPV was estimated to range between 0.18% and 0.56%. We have provided this information in the revised manuscript as follows: ‘The positive predictive value (PPV) was primarily calculated to be 0.18% (88/47,962). This value might have been an underestimation, because the cases that could be followed up were 16,734 (34.9%). Thus, the maximum PPV was calculated as 0.56% (88/16734), which might have been an overestimation. Plausible PPV was estimated to range between 0.18% and 0.56%.’ (Lines 171–175) Moreover, we have revised the data presented in Tables 2 and 3. 2. According to the estimation by the authors (line 172 of the manuscript), the expected incidence of active TB for the population studied was 9.1/100000. However, the rate of detection was 1.8/100000. That means more than 80% of the cases of active were not detected by annual chest x-ray examination. With an extremely low positive predictive value (0.53%), it is difficult to appreciate the usefulness of routine annual chest x-ray examination for the purpose of TB detection in countries with low prevalence of TB. The variability and reproducibility were well-known issues for chest x-ray interpretation. If an outbreak of clustered transmission among work place occurs, retrospective re-evaluation of the chest x-ray with a documented diagnosis in mind may reveal some obscured abnormalities and cause trouble to the radiologist who firsthand interpreted the chest x-ray. Similar issues existed in the interpretation of usefulness of lung cancer detection with chest x-ray. At least, these concerns should be listed. Response: We would like to thank the reviewer for the comment. Indeed, the estimated prevalence of tuberculosis was 9.1/100,000 persons, and the detection rate on chest X-rays was 1.8/100,000 persons. The estimated prevalence of lung cancer was 41.0/100,000 persons, while the detection rate was 9.1/100,000 persons. Since the detection rate of chest X-rays is considered to be limited, we have revised the corresponding part in the Discussion section as follows: (Before editing) Line 247-250: Considering the statistics from the national database and the natural course of TB, CXR examination in periodic workplace health examinations could be expected to actually play a role to some extent in the detection of active TB in clinical practice. However, the contribution of CXR to tuberculosis infection control might not be deemed essential. Line 329-330: In conclusion, based on the actual rate of detection of TB using CXR, we ascertained that CXR plays a certain role in TB detection at the workplace. (After editing) ‘Considering the national database statistics and the natural course of TB, it is difficult to appreciate the usefulness of routine annual CXR examination to detect TB in countries with low TB prevalence. Thus, the contribution of CXR to tuberculosis infection control might not be significant.’. (Lines 262–265) ‘In conclusion, based on the actual detection rate of TB using CXR, we ascertained that CXR plays a little role in TB detection in the general workplace. In addition, variability and reproducibility are well-known issues for CXR interpretation. If an outbreak of clustered transmission occurs in the workplace or if some LC cases are overlooked, retrospective re-evaluation of cases with a documented diagnosis who were previously evaluated using CXR may reveal discrepancies and create issues for the radiologist who interpreted the CXR’. (Lines 348–353) 3. The expected incidence of lung cancer increases exponentially in the elderly. I suggest the authors to extend the table 3 by further stratifying the detection of lung cancer among age groups of <40, 40-60, and >60 years old. Response: Please note that those who underwent CXR examination were aged ≤60 years, as the retirement age was at 60 years in 2016. Thus, the number of those aged >60 years was negligible. 4. The table 5 is not quite relevant to the topics of the present study. It is difficult to determine the accuracy, sensitivity, and specificity by chest x-ray examination for the diagnoses listed. I would suggest to remove the information of table 5 from the present report. Response: We would like to thank the reviewer for the constructive comment. According to the reviewer’s suggestions, we have revised our manuscript and removed the information presented in Table 5. Examination of chest X-rays at workplace aimed to screen tuberculosis and lung cancer. Thus, this study included descriptive information regarding the observed stage of disease according to CXR findings. Therefore, we have moved this Table to the Supplementary files. 5. In line 256-258, the sentence “From the perspective of cost-effectiveness, screening for Tb should be considered when the prevalence is lower than 10 per 100,000 persons” is ambiguous. Response: We would like to thank the reviewer for the comment. Please note that we have revised this part as follows: ‘The World Health Organisation aims to reduce the new TB cases by approximately 90% by 2035 and reduce the prevalence to <10 per 100,000 population [19]. From the perspective of cost-effectiveness, active case-findings for TB using CXR should be considered among high-risk populations. Nevertheless, the strategy should be re-considered when the prevalence is <10 per 100,000 persons in Japan [20]. Active case-findings among all general workers may be unnecessary.’. (Lines 271–277) Reviewer #2: Numbers of diagnoses and stage are poor surrogate outcomes for the effect of health checks. Increased numbers of diagnosis and more localised stages can be and impact of a beneficial effect, a harmful effect (especially overdiagnosis) or both. Moreover, mortality rates in a non-randomised trial cannot be used as a result of benefits. Finally, survival rates will be biased due to lead time bias and leangt time bias (overdiagnosis bias) and are the not useful outcomes when it comes to early disease detection, e.g. screening and health checks. Response: The authors would like to thank the reviewer for the constructive feedback and suggestions to improve the manuscript. We have made every effort to address the issues raised and to respond to the reviewer’s comments. The revisions are indicated in red color text in the revised manuscript. In addition, we have carried our English check by the native speakers again. We fully understood that the evaluation of screening such as cancer screening should be based on the first priority demonstrating its effectiveness as screening by randomized controlled trials. Many studies have already conducted studies on the effectiveness of chest X-rays on lung cancer screening. However, it is only an evaluation of the effectiveness of a screening method by experimental research protocols with limited sample size. Thus, to evaluate usefulness as a measure, a realistic evaluation when implemented in society is also necessary. The purpose of this study is to provide actual descriptive data on the current state of social implementation of the screening as a measure, not to evaluate the effectiveness of the screening. It only shows social significance. Please note that we have added the following part to the Introduction section of the revised manuscript to address the issues raised by the reviewer and to clearly describe our purpose: ‘The effectiveness for screening diseases such as cancer should be determined with randomised controlled trials using mortality as the outcome. The Japanese guidelines for lung cancer screening recommend the performance of CXR [9]. However, these guidelines were developed based on the findings of experimental studies with a limited sample size that evaluated the effectiveness of screening methods. Thus, to evaluate significance as a measure, a realistic evaluation when implemented in a large population is also needed. The purpose of this study was to provide actual descriptive data on the current state of social implementation of screening, and not to evaluate the effectiveness of the screening method.’. (Lines 67–74) Submitted filename: response_210615.docx Click here for additional data file. 27 Oct 2021 PONE-D-20-19580R1Descriptive study of chest x-ray examination in mandatory annual health examinations at the workplace in JapanPLOS ONE Dear Dr. Tatemichi, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Since Reviewer 2 was not adequately satisfied with your previous review, I refer you to request a further review by asking you to focus on the responses to Reviewer 2. Please submit your revised manuscript by Dec 11 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols. We look forward to receiving your revised manuscript. Kind regards, Alessandra Giuliani Academic Editor PLOS ONE Additional Editor Comments (if provided): Dear authors, Since Reviewer 2 was not adequately satisfied with your previous review, I refer you to request a further review by asking you to focus on the responses to Reviewer 2. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: All comments have been addressed Reviewer #2: (No Response) ********** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: No ********** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: N/A ********** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: Yes ********** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ********** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: Thank you. All comments were addressed appropriately. I believe this revision is appropriate to be accepted for publication. Reviewer #2: The authors have not responded adequately to my previous critique and have not changed their interpretation of the outcomes of numbers of diagnoses and stage, e.g. the authors have not discussed the possibility of overdiagnosis at all. Their conclusion is also unchanged and is most likely not right. ********** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: Yes: Chih-Hsin Lee Reviewer #2: Yes: John Brodersen [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. 25 Nov 2021 The authors would like to thank the reviewer for the constructive feedback and suggestions to improve the manuscript. We have made every effort to address the issues raised and to respond to the reviewer’s comments. The revisions are indicated in red font in the revised manuscript. Please note that we have revised the following part to the Abstract, Introduction, and Discussion section of the revised manuscript to address the issues raised by the reviewer and to describe our purpose clearly: As the reviewer mentioned, the numbers of the detection and early-stage cancer are generally not useful outcomes, mainly because they can include cases with overdiagnosis. Particularly the problem of LDCT-based lung cancer screening is overdiagnosis. Thus, the effectiveness for screening diseases such as cancer must be determined with randomised controlled trials using mortality as the outcome. Lung cancer screening with CXR is conducted based on evidence of the effect on reduction of mortality. However, in CXR, the problem of sensitivity is greater than the problem of overdiagnosis in terms of screening efficacy. The purpose of this study was to provide actual descriptive data on the current state of social implementation of screening among workers and not to evaluate the effectiveness of the screening method. Our study investigated the detection rate and early cancer detection rate in medical examinations that have already been implemented as a law in the workplace for public health. Therefore, we revised our interpretation and conclusion according to reviewer’s comments. This revision appears in red font. Abstract Before: L17-18: This study aimed to assess the clinical utility of chest X-ray examination in the workplace and provide basic data to consider future policies for mandatory annual health examinations. Revised: L17-18: This study aimed to provide basic data to consider future policies for mandatory annual health examinations in the workplace. Before; L36-38 Early-stage lung cancer can also be detected among workers by Chest x-ray examinations. However, low-dose computed tomography may be superior for lung cancer screening because it can detect twice as many cases as chest radiography. Revised: L34-38: With regard to LC screening, the detection rate of LC was lower, approximately 50%, than the expected rate (41.0 per 100,000 persons) of LC morbidity based on the age-sex distribution of this study population. However, the role of CXR for LC screening cannot be mentioned based on this result because assessment of mortality reduction is essential to evaluate. Introduction Before: L66-73 The effectiveness for screening diseases such as cancer should be determined with randomised controlled trials using mortality as the outcome. The Japanese guidelines for lung cancer screening recommend the performance of CXR [9]. However, these guidelines were developed based on the findings of experimental studies with a limited sample size that evaluated the effectiveness of screening methods. Thus, to evaluate significance as a measure, a realistic evaluation when implemented in a large population is also needed. The purpose of this study was to provide actual descriptive data on the current state of social implementation of screening, and not to evaluate the effectiveness of the screening method. Revised: L66-74 Japanese guideline for lung cancer screening recommends CXR [9]. Thus mandatory CXR in workplace plays a role in lung cancer screening in addition to screening for TB. The first priority of evaluation of effectiveness on cancer screening must be based on randomized controlled trials (RCT) using mortality as an outcome. Theoretically, the detection number of cancers is not a useful outcome to evaluate effectiveness because cancers detected by screening can include cases with overdiagnosis. Thus this study did not aim to evaluate the effectiveness of CXR for cancer screening. The purpose of this study is to provide actual descriptive data on the current state of social implementation of the screening as a measure, not directly to assess the effectiveness of CXR for cancer screening. Discussion Before: L293-294 Merely by considering this result, the early-stage detection rate with LDCT was two times higher than that by CXR. Revised: L287-293 However, outcomes for the effect of cancer screening must be addressed by mortality, but not by increased numbers of diagnoses and more localized stages, because cancer screening has several biases and harmful effects such as overdiagnosis [23,24]. Regarding LC screening, the main problem of CXR examination was reported to be a low sensitivity while that of LDCT was overdiagnosis [25]. Thus, using our data on this study, we cannot compare or evaluate the screening effects between CXR and LDCT. We only provided descriptive data as reference values. References Three references have been added. 23. Brawley OW, Kramer BS. Cancer screening in theory and in practice. J Clin Oncol 2005;23:293-300. 24. Raffle A, Gray M. Screening: evidence and practice. Oxford University Press, 2007. 25. T Sobue 1, T Suzuki, M Matsuda, T Horai, A Kajita, K Kuriyama, M Fukuoka, Y Kusunoki, M Kikui, S Ryu, et al. Sensitivity and specificity of lung cancer screening in Osaka, Japan. Jpn J Cancer Res. 1991;82(10):1069-76. Before: L298-299 ‘’Moreover, this finding indicated that the utility of LDCT for screening for LC was almost twice as high as that of CXR.’’ Revised: This sentence has been deleted. Before: L337-338 We could not effectively compare the usefulness of CXR and LDCT. Revised: L335-339 This is because all CXR in Japan has historically been started and performed as TB screening for workers. The number of detections as cancer screening cannot be evaluated due to problems of harmful effects such as overdiagnosis. Thus, we could not effectively compare the usefulness of CXR and LDCT only based on our results. Before: L351-358 With regard to LC screening, the detection rate with CXR was lower than that with LDCT, and the detection rate in Stage I using CXR, when detection may save lives, was approximately 50% lower than that using LDCT. These findings were consistent with those of a previous residence-based comparative study by Nawa et al [23]. Nevertheless, our results do not support the recommendation for the exclusion of CXR from the mandatory annual health examinations; however, effective introduction of LDCT screening to workplace health examinations should be considered as a substitute for CXR for LC screening in the future. Revised: L352-359 With regard to LC screening, the detection rate with CXR was lower, approximately 50%, than the expected rate of LC morbidity based on the age-sex distribution of this study population. However, the results of this study do not evaluate the actual utility of CXR in the mandatory annual health examinations. Further follow-up studies are needed to assess mortality reduction in workplace for LC screening. Inductions of LDCT are discussed for LC screening worldwide, the effective introduction of LDCT screening to workplace health examinations should be considered in the future, based on the evidence by RCT in Japan. Submitted filename: response_2021.11.25.docx Click here for additional data file. 14 Dec 2021 PONE-D-20-19580R2Descriptive study of chest x-ray examination in mandatory annual health examinations at the workplace in JapanPLOS ONE Dear Dr. Tatemichi, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. In the Conclusion section of this revised version. The sentence is ambiguous: "Inductions of LDCT are discussing for LC screening worldwidely...". Please revise it for clarity. Please submit your revised manuscript by Jan 28 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript:If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols. We look forward to receiving your revised manuscript. Kind regards, Alessandra Giuliani Academic Editor PLOS ONE Journal Requirements: Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. Additional Editor Comments (if provided): In the Conclusion section of this revised version. The sentence is ambiguous: "Inductions of LDCT are discussing for LC screening worldwidely...". Please revise it for clarity. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: All comments have been addressed ********** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes ********** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes ********** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes ********** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes ********** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: In the Conclusion section of this revised version. The sentence is ambiguous: "Inductions of LDCT are discussing for LC screening worldwidely...". Please revise it for clarity. ********** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: Yes: Chih-Hsin Lee [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. 20 Dec 2021 Reviewer #1: In the Conclusion section of this revised version. The sentence is ambiguous: "Inductions of LDCT are discussing for LC screening worldwidely...". Please revise it for clarity. Response: We would like to appreciate the Reviewers and the Editorial Board for taking the time to review our manuscript and thank their constructive and thoughtful comments. According to the suggestion, we have revised our manuscript below. Conclusion Before: L357-359: Inductions of LDCT are discussing for LC screening worldwidely, effective introduction of LDCT screening to workplace health examinations should be considered in the future, based on the evidence by RCT in Japan. Revised: L357-362: Reports from North America have shown a significant reduction of mortality regarding LDCT screening, and it will be considered in high-risk populations, such as those over 50 years with heavy smokers in workplaces. Our study, however, demonstrated that the effectiveness of LDCT screening was limited for patients with small cell carcinoma. Thus, strengthening smoking cessation measures in workplaces should be considered as well as screening. Submitted filename: response_2021.12.19.docx Click here for additional data file. 27 Dec 2021 Descriptive study of chest x-ray examination in mandatory annual health examinations at the workplace in Japan PONE-D-20-19580R3 Dear Dr. Tatemichi, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Alessandra Giuliani Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: 4 Jan 2022 PONE-D-20-19580R3 Descriptive study of chest x-ray examination in mandatory annual health examinations at the workplace in Japan Dear Dr. Tatemichi: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Alessandra Giuliani Academic Editor PLOS ONE
  23 in total

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Authors:  Jan P van Meerbeeck; Dean A Fennell; Dirk K M De Ruysscher
Journal:  Lancet       Date:  2011-05-10       Impact factor: 79.321

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Authors:  Matthijs Oudkerk; Anand Devaraj; Rozemarijn Vliegenthart; Thomas Henzler; Helmut Prosch; Claus P Heussel; Gorka Bastarrika; Nicola Sverzellati; Mario Mascalchi; Stefan Delorme; David R Baldwin; Matthew E Callister; Nikolaus Becker; Marjolein A Heuvelmans; Witold Rzyman; Maurizio V Infante; Ugo Pastorino; Jesper H Pedersen; Eugenio Paci; Stephen W Duffy; Harry de Koning; John K Field
Journal:  Lancet Oncol       Date:  2017-12       Impact factor: 41.316

Review 3.  Low-dose CT screening can reduce cancer mortality: A meta-analysis.

Authors:  Xue Tang; Guangbo Qu; Lingling Wang; Wei Wu; Yehuan Sun
Journal:  Rev Assoc Med Bras (1992)       Date:  2019-12       Impact factor: 1.209

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Journal:  Lancet       Date:  2019-03-20       Impact factor: 79.321

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Authors:  Julius Matthias Weinrich; Roland Diel; Markus Sauer; Frank Oliver Henes; Karen Meywald-Walter; Gerhard Adam; Gerhard Schön; Peter Bannas
Journal:  Eur Radiol       Date:  2017-01-03       Impact factor: 5.315

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Authors:  Nader Ghotbi; Shuzo Nishimura; Naoyoshi Takatsuka
Journal:  Environ Health Prev Med       Date:  2005-07       Impact factor: 3.674

Review 7.  Low-dose computed tomography screening in Japan.

Authors:  Takeshi Nawa; Tohru Nakagawa; Tetsuya Mizoue; Katsuyuki Endo
Journal:  J Thorac Imaging       Date:  2015-03       Impact factor: 3.000

8.  A decrease in lung cancer mortality following the introduction of low-dose chest CT screening in Hitachi, Japan.

Authors:  Takeshi Nawa; Tohru Nakagawa; Tetsuya Mizoue; Suzushi Kusano; Tatsuya Chonan; Kenji Hayashihara; Tetsushi Suito; Katsuyuki Endo
Journal:  Lung Cancer       Date:  2012-10-12       Impact factor: 5.705

9.  Chest roentgenogram in pulmonary tuberculosis. New data on an old test.

Authors:  P F Barnes; T D Verdegem; L A Vachon; J M Leedom; G D Overturf
Journal:  Chest       Date:  1988-08       Impact factor: 9.410

10.  Sensitivity and specificity of lung cancer screening in Osaka, Japan.

Authors:  T Sobue; T Suzuki; M Matsuda; T Horai; A Kajita; K Kuriyama; M Fukuoka; Y Kusunoki; M Kikui; S Ryu
Journal:  Jpn J Cancer Res       Date:  1991-10
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1.  Effect of employers' concerns about cancer countermeasures on the implementation of cancer screening and support for balancing cancer treatment and work in small and medium-sized Japanese enterprises.

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Journal:  J Occup Health       Date:  2022-01       Impact factor: 2.570

2.  Artificial Intelligence-Based Identification of Normal Chest Radiographs: A Simulation Study in a Multicenter Health Screening Cohort.

Authors:  Hyunsuk Yoo; Eun Young Kim; Hyungjin Kim; Ye Ra Choi; Moon Young Kim; Sung Ho Hwang; Young Joong Kim; Young Jun Cho; Kwang Nam Jin
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